Constructing a Prognostic Model of Uterine Corpus Endometrial Carcinoma and Predicting Drug-Sensitivity Responses Using Programmed Cell Death-Related Pathways.

Background: Uterine Corpus Endometrial Carcinoma (UCEC) is the most common type of cancer that develops in the uterus, specifically originating from the endometrium, the inner lining of the uterus. Programmed cell death (PCD) is a highly regulated process that eliminates damaged, aged, or unwanted cells in the body. Dysregulation of PCD pathways can contribute to the formation and progression of various cancers, including UCEC. Methods: Fourteen PCD pathways (autophagy-dependent cell death, alkaliptosis, apoptosis, cuproptosis, entotic cell death, ferroptosis, immunogenic cell death, lysosome-dependent cell death, MPT-driven necrosis, necroptosis, netotic cell death, oxeiptosis, parthanatos, and pyroptosis) were involved in building a prognostic signature. The model was trained and tested using data from the TCGA-UCEC and validated with the GSE119041 dataset. Results: A 12-gene PCD signature (DRAM1, ELAPOR1, MAPT, TRIM58, UCHL1, CDKN2A, CYFIP2, AKT2, LINC00618, TTPA, TRIM46, and NOS2) was established and validated in an independent dataset. UCEC patients with a high PCD score (PCDS) exhibited worse prognosis. Furthermore, PCDS was found to be associated with immune related cells and key tumor microenvironment components through multiple methods. It was observed that UCEC patients with a high PCD score may not benefit from immunotherapy, but some chemo drugs like Bortezomib may be useful. Conclusion: In conclusion, a novel PCD model was established by comprehensively analyzing diverse cell death patterns. This model accurately predicts the clinical prognosis and drug sensitivity of UCEC. The findings suggest that the PCD signature can serve as a valuable tool in assessing prognosis and guiding treatment decisions for UCEC patients.

Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells.

Hepatic fibrosis is a complex chronic liver disease in which both macrophages and hepatic stellate cells (HSCs) play important roles. Many studies have shown that clodronate liposomes (CLD-lipos) effectively deplete macrophages. However, no liposomes have been developed that target both HSCs and macrophages. This study aimed to evaluate the therapeutic efficacy of lipopolysaccharide-coupled clodronate liposomes (LPS-CLD-lipos) and the effects of liposomes size on hepatic fibrosis. Three rat models of hepatic fibrosis were established in vivo; diethylnitrosamine (DEN), bile duct ligation (BDL), and carbon tetrachloride (CCl4). Hematoxylin and eosin staining and serological liver function indices were used to analyze pathological liver damage. Masson's trichrome and Sirius red staining were used to evaluate the effect of liposomes on liver collagen fibers. The hydroxyproline content in liver tissues was determined. In vitro cell counting kit-8 (CCK-8) and immunofluorescence assays were used to further explore the effects of LPS modification and liposomes size on the killing of macrophages and HSCs. Both in vitro and in vivo experiments showed that 200 nm LPS-CLD-lipos significantly inhibited hepatic fibrosis and the abnormal deposition of collagen fibers in the liver and improved the related indicators of liver function. Further results showed that 200 nm LPS-CLD-lipos increased the clearance of macrophages and induced apoptosis of hepatic stellate cells, significantly. The present study demonstrated that 200 nm LPS-CLD-lipos could significantly inhibit hepatic fibrosis and improve liver function-related indices and this study may provide novel ideas and directions for hepatic fibrosis treatment.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice.

Aging is always accompanied by chronic diseases which probably attribute to long-term chronic inflammation in the aging body. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, immunosuppressive properties of aged MSCs are found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes-associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1). YAP1 regulates the transcription of STAT1 through binding with its promoter. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs is revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.

Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4.

Background: Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism. Methods: To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS. Results: We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway. Conclusion: In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway.

Novel characteristics for immunophenotype, FISH pattern and molecular cytogenetics in synovial sarcoma.

As a rare and highly aggressive soft tissue sarcoma, the new immunophenotype, atypical FISH pattern and relevant molecular cytogenetics of synovial sarcoma (SS) remain less known, although it is characteristically represented by a pathognomonic chromosomal translocation t (X; 18) (p11.2; q11.2). Methodologically, the morphology was retrospectively analysed by using H&E staining, and immunohistochemical features were investigated by using markers that have been recently applied in other soft tissue tumors. Moreover, FISH signals for SS18 and EWSR-1 break-apart probes were examined. Finally, cytogenetic characteristics were analysed via RT-PCR and Sanger sequencing. Consequently, nine out of thirteen cases that were histologically highly suspected as SS were finally identified as SS via molecular analysis. Histologically, nine SS cases were divided into monophasic fibrous SS (4/9), biphasic SS (4/9) and poorly differentiated SS (1/9). Immunohistochemically, SOX-2 immunostaining was positive in eight cases (8/9) and PAX-7 immunostaining was diffusely positive in the epithelial component of biphasic SS (4/4). Nine cases showed negative immunostaining for NKX3.1 and reduced or absent immunostaining for INI-1. Eight cases showed typically positive FISH signalling for the SS18 break-apart probe, whereas one case exhibited an atypical FISH pattern (complete loss of green signalling, case 2). Furthermore, the SS18-SSX1 and SS18-SSX2 fusion genes were identified in seven cases and two cases, respectively. The fusion site in 8 out of 9 cases was common in the literature, whereas the fusion site in case 2 was involved in exon 10 codon 404 in SS18 and exon 7 codon 119 in SSX1 (which has not been previously reported), which notably corresponded to the complete loss of green signalling in the FISH pattern. Additionally, FISH analysis of the EWSR-1 gene in nine SS cases demonstrated aberrant signalling in three cases that were recognized as a monoallelic loss of EWSR-1 (1/9), an amplification of EWSR-1 (1/9) and a translocation of EWSR-1 (1/9). In conclusion, SS18-SSX fusion gene sequencing is obligatory for a precise diagnosis of SS when dealing with a confusing immunophenotype and atypical or aberrant FISH signalling for SS18 and EWSR-1 detection.

Biomimetic Periodontal Ligament Transplantation Activated by Gold Nanoparticles Protects Alveolar Bone.

Stem cell therapy might be a promising method to stimulate alveolar bone regeneration, which is currently a major clinical challenge. However, its therapeutic features largely depend on pretreatment and transplantation preparation. Herein, a novel biomimetic periodontal ligament transplantation composed of human periodontal ligament stem cells (hPDLSCs) pretreated with gold nanocomplexes (AuNCs) and embedded in a type-I collagen hydrogel scaffold is developed to protect alveolar bone from resorption. AuNCs are readily absorbed by primary hPDLSCs, with limited cytotoxicity, and promote osteogenic differentiation of hPDLSCs effectively in vitro. In addition, the AuNCs-induced hPDLSCs are encapsulated with type-I collagen hydrogel scaffold to mimic their native physiological niche, and then are transplanted into a rat model of alveolar bone resorption. Both micro-computed tomography (micro-CT) and immunohistochemical assays demonstrate that alveolar bone loss is significantly prevented. Furthermore, the underlying therapeutic mechanism is elucidated, in which transplantation-activated osteogenesis is associated with autophagy, which enables bone remodeling and regeneration. This study provides critical insight into the role of PDLSCs in bone homeostasis and proposes an innovative AuNCs-based strategy for stem cell therapy in bone regeneration.

Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment.

Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.

Balance training benefits chronic ankle instability with generalized joint hypermobility: a prospective cohort study.

BACKGROUND: Balance training is the first choice of treatment for chronic ankle instability (CAI). However, there is a lack of research on the effects of balance training in CAI with generalized joint hypermobility (GJH). This study is to compare the outcomes of balance training in CAI patients with and without GJH. METHODS: Forty CAI patients were assigned into the GJH group (Beighton ≥ 4, 20) and non-GJH group (Beighton < 4, 20) and they received same 3-month supervised balance training. Repeated measure ANOVA and independent t test were used to analyze self-reported questionnaires (Foot and ankle ability measure, FAAM), the number of patients experiencing ankle sprain, isokinetic muscle strength and postural control tests (Star excursion balance test, SEBT and Balance errors system, BES) before training, post-training immediately, and post-training 3 months, respectively. RESULTS: At baseline, no differences were found between groups with except for GJH group having poorer SEBT in the posteromedial direction (83.6 ± 10.1 vs 92.8 ± 12.3, %) and in the posterolateral direction (84.7 ± 11.7 vs 95.7 ± 8.7, %). Following the balance training, GJH group demonstrated lower re-sprain ratio (immediately after training, 11.1% vs 23.5%, 3 month after training, 16.7% vs 29.4%) than non-GJH group, as well as greater FAAM-S score, plantarflexion strength and dorsiflexion strength at post-training immediately and 3 months, and both groups improved similarly in the FAAM-A score, muscle strength and balance control (SEBT in the posterior-lateral and posterior-medial directions, and BES scores) compared with baseline. CONCLUSIONS: CAI patients with GJH gained equally even better postural stability and muscle strength after the balance training than the non-GJH patients. Balance training could still be an effective treatment for CAI patients with GJH before considering surgery. TRIAL REGISTRATION: ChiCTR1900023999, June 21st, 2019.

AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.

BACKGROUND AND AIMS: Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. APPROACH AND RESULTS: Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1 + CSF1R + MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C-C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up-regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. CONCLUSIONS: Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.

Transcriptome sequencing and gas chromatography-mass spectrometry analyses provide insights into ß-caryophyllene biosynthesis in Brassica campestris.

Sesquiterpenes are important defensive secondary metabolites and aroma components. However, limited information is available on the mechanism of sesquiterpene formation and composition in the non-heading Chinese cabbage (NHCC) leaf. Therefore, headspace solid-phase microextraction/gas chromatography-mass spectrometry (HS-SPME/GC-MS) combined with transcriptome analysis was used to study the mechanism of volatile organic compound formation. A total of 26 volatile organic compounds were identified in two NHCC cultivars 'SZQ' and 'XQC' and their F1 hybrids. Among these, sesquiterpene ß-caryophyllene was identified only in 'XQC' and F1. Five genes encoding caryophyllene synthase were identified. The candidate ß-caryophyllene synthase genes BcTPSa11 and BcTPSa21 had high expression levels only in 'XQC' and F1. In addition, several transcription factors of MYB-related, MYB, bHLH, and AP2/ERF families were identified by co-expression, suggesting that they regulate ß-caryophyllene biosynthesis. Our results provide a molecular basis for sesquiterpene biosynthesis as well as insights into the regulatory network of ß-caryophyllene in NHCC.

Efficacy of astragalus in the treatment of radiation-induced lung injury based on traditional Chinese medicine: A systematic review and meta-analysis of 25 RCTs.

BACKGROUND: Astragalus (Hedysarum Multijugum Maxim., Huangqi) is a Chinese herbal medicine, and according to the theory of traditional Chinese medicine (TCM), Chinese medicinal preparations containing astragalus can be used clinically to treat radiation-induced lung injury (RILI). To systematically review the efficacy and safety of Chinese medicinal preparations containing astragalus in the prevention and treatment of RILI by means of meta-analysis. METHODS: A systematic literature on randomized controlled trials (RCTs) of prescriptions containing astragalus in the treatment of RILI by Pubmed, Embase, Web of Science, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal Database, WANFANG Database. The retrieval time is from the establishment of the database to January 18, 2022. Meta-analysis, heterogeneity test and sensitivity analysis were performed on eligible RCTs using Revman 5.4 software and STATA 17.0 software, and a "funnel plot" was used to analyze potential publication bias. RESULTS: A total of 25 RCTs were included, including 1762 patients, and the most widely used drugs were heat-clearing and detoxifying, yin-nourishing and qi-nourishing. The prescriptions containing astragalus can significantly reduce the total incidence of RILI (P < .01), improve the total effective rate and cure rate of RILI (P < .01), improve the quality of life of patients, alleviate breathing difficulties and reduce the expression of inflammatory factors (P < .01), and no adverse reactions related to TCM treatment were reported. CONCLUSION: The traditional Chinese medicinal preparation containing astragalus can effectively alleviate the clinical symptoms of RILI, reduce the toxic side effects, and is safe to use in clinic.

3,5,3'-Triiodothyronine-Loaded Liposomes Inhibit Hepatocarcinogenesis Via Inflammation-Associated Macrophages.

Background: Hepatocellular carcinoma (HCC) is inflammation-related cancer. Persistent inflammatory injury of the liver is an important factor mediating the occurrence and development of liver cancer. Hepatic macrophages play an important role in the inflammatory microenvironment, which mediates tumor immune escape, tumor growth, and metastasis. Previous studies have suggested that L-3,5,3-triiodothyronine (T3) can regulate inflammation; however, its use is associated with serious cardiac side effects, and its role in hepatocarcinogenesis remains unclear. In this study, we aimed to develop an effective T3 delivery system with reduced cardiac toxicity and to explore its effects on HCC occurrence. Methods: T3 liposomes (T3-lipo) were prepared using the thin-film hydration method, and their characteristics, including particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading, drug release, and stability, were evaluated in vitro. We assessed the effect of T3-lipo on hepatocarcinogenesis in diethylnitrosamine (DEN)-induced primary HCC in rats and examined the biodistribution of T3 and T3-lipo by high-performance liquid chromatography-mass spectrometry. Furthermore, we explored the potential molecular mechanism of T3-lipo in hepatocarcinogenesis by immunohistochemistry and immunofluorescence analyses, Bio-Plex assays, real-time polymerase chain reaction analysis, and Western blotting assays. Results: Compared with T3, T3-lipo had an enhanced inhibitory effect on hepatocarcinogenesis and reduced cardiac side effects in DEN-induced primary HCC in rats. Mechanistically, T3-lipo were absorbed by hepatic macrophages and regulated the secretion of inflammatory cytokines in macrophages by inhibiting inflammatory signaling pathways. Conclusions: T3-lipo may suppress hepatocarcinogenesis by regulating the inflammatory microenvironment in the liver and reduce the cardiac side effects meanwhile.

Arthroscopic modified Broström procedure achieves faster return to sports than open procedure for chronic ankle instability.

PURPOSE: To compare the clinical outcomes, rate of return to sports, postural control, and muscle strength between the arthroscopic and open modified Broström procedure for chronic lateral ankle instability (CLAI) patients. METHODS: From September 2018 to April 2019, 70 patients diagnosed with CLAI were prospectively included with arthroscopic modified Broström procedure (n = 36) and open modified Broström procedure (n = 34). They were evaluated at five time points (preoperation and 3 months, 6 months, 1 year and 2 years postoperatively). The main results examined the rate of return to sports, American Orthopaedic Foot and Ankle Society Score (AOFAS), Foot and Ankle Ability Measure (FAAM), visual analogue scale (VAS), centre of pressure (COP) excursion velocity, time to boundary (TTB), plantar pressure, isokinetic muscle strength and complications. RESULTS: Compared with the open group, the arthroscopic group demonstrated a significantly shorter period of return to the preinjury sport (13.2 ± 2.4 weeks vs. 18.7 ± 3.1 weeks, P = 0.023) and a higher early sport ratio (80.6 vs. 61.8%, P = 0.011) combined with better FAAM sports and AOFAS at 3 months and 6 months postoperatively and VAS at 3 months postoperatively. In addition, better anterior-posterior postural control stability, less time to peak force under lateral hindfoot and better dorsiflexion strength were shown in the arthroscopic group at 6 months postoperatively. No significant difference was found in clinical scores, posture control or muscle strength at the 1- or 2-year follow-up between the two groups. CONCLUSIONS: Shorter period and higher rates of return to sport activities and better clinical scores, posture control and muscle strength were achieved in the arthroscopic group at 6 months postoperatively, and no clinical differences were found between arthroscopic and open modified Broström procedure 1 year or 2 years postoperatively. Arthroscopic modified Broström procedure is a reliable procedure for CLAI injuries with the demand for fast exercise recovery. CLINICAL REGISTRATION: ChiCTR1900023999. LEVEL OF EVIDENCE: II.

The L-shaped tunnel technique showed favourable outcomes similar to those of the Y-graft technique in anatomic lateral ankle ligament reconstruction.

PURPOSE: To compare the mid- to long-term clinical and radiological outcomes of the confluent L-shaped tunnel technique with the Y-graft technique for anatomic lateral ankle ligament reconstruction. METHODS: This retrospective study involved 41 patients who underwent lateral ankle ligament reconstruction between 2013 and 2018. Based on the tunnel direction and tendon fixation method at the fibula side, patients were divided into two groups, with 17 patients in the L-shaped tunnel group and 24 patients in the Y-graft group. The American Orthopaedic Foot and Ankle Society (AOFAS) score, visual analogue scale (VAS) pain score, Tegner score, and Karlsson score were evaluated and compared preoperatively and at follow-up. Anterior talar translation and talar tilt at stress radiographs, postoperative sprain recurrence, range of motion (ROM) restriction, sensory disturbance, etc., were also collected and compared. RESULTS: The mean follow-up times were 72 and 42 months for the L-shaped group and Y-graft group, respectively. The median VAS pain score, Tegner score, AOFAS score, Karlsson score significantly improved from a preoperative level in both groups (all with p < 0.01). No significant difference was found between the two groups regarding the changes from preoperatively to postoperatively except for the VAS pain score reduction (1.58 ± 1.58 in the L-shaped group vs. 2.53 ± 1.29 in the Y-graft group, p = 0.035). The incidence of flexion-extension ROM restriction (≥ 5°) was significantly higher in the Y-graft group (41.2%) than in the L-shaped group (12.5%) (p = 0.035). CONCLUSIONS: Both the confluent L-shaped tunnel technique and the Y-graft technique significantly improved symptoms, ankle function, and radiographic outcomes in patients with chronic lateral ankle instability (CLAI) at mid- to long-term follow-up. The confluent L-shaped tunnel technique resulted in lower rates of flexion-extension ROM restriction, while the Y-graft technique showed better VAS pain reduction. This result could provide further evidence for the surgical treatment of CLAI. LEVEL OF EVIDENCE: III.

In Vivo Micro-Computerized Tomography Tracking of Human Periodontal Ligament Stem Cells Labeled with Gold Nanocomplexes.

Gold nanocomplexes have been proposed as contrast agents for computerized tomography (CT) and cell tracking, which is especially useful in stem cell therapy. However, their potential for long-term in vivo cell detection is still unknown. This study proposes an optimized approach to labeling human periodontal ligament stem cells (hPDLSCs) with gold nanocomplexes to evaluate their detection with micro-CT after transplantation at four different rat tissues. The gold nanocomplexes of 0.05 mg mL-1 do not affect cell viability nor osteogenic differentiation capacity, but render fluorescent and radiopaque hPDLSCs. Excellent linear correlation with the number of labeled cells is shown over a wide range (r = 0.99, P < 0.01), with a detection limit of ≈1.2 × 103 cells/µL. In vivo, strong, and durable detection of transplanted labeled cells within 5 days at all investigated areas is seen by micro-CT and immunohistochemical assay. This approach confirms the potential of gold nanocomplexes in longitudinal in vivo cell tracking, which may facilitate their application in CT image-guided interventions commonly used in oromaxillofacial or systemic applications of stem cell therapy.

The stemness of hepatocytes is maintained by high levels of lipopolysaccharide via YAP1 activation.

BACKGROUND: The liver possesses a powerful regeneration ability, which is correlated with the stemness of hepatocytes in the portal vein (PV). However, the mechanism underlying the maintenance of hepatocyte stemness has not been elucidated. Here, we hypothesized that high levels of lipopolysaccharide from the portal vein might maintain the stemness of hepatocytes in the PV area. METHODS: First, we examined the location of hepatic stem cells and the concentration of lipopolysaccharide (LPS) in the portal vein and inferior vena cava. Then, we assessed the effect of LPS on stemness maintenance in mice by using antibiotics to eliminate LPS and knocking out the LPS receptor, TLR4. In vitro, the effect of LPS on the stemness of hepatocytes was investigated by colony and sphere formation assays and assessment of pluripotent and stem cell marker expression. Furthermore, we studied the mechanism by which LPS regulates the stemness of hepatocytes. Finally, we ligated the portal vein branch to further verify the effect of LPS. RESULTS: We found that a high level of LPS from the portal vein was correlated with the location of hepatic stem cells in the PV area, and elimination of LPS by antibiotics inhibited the expression of the stemness marker. LPS promoted colony and sphere formation and induced the upregulation of pluripotent and stem cell markers in AML12 cells. Furthermore, in the reprogramming medium, LPS facilitated the dedifferentiation of mature hepatocytes into hepatic progenitor-like cells, which exhibited a bipotent differentiation capacity in vivo and in vitro. Mechanistically, LPS bound TLR4 to regulate stemness of hepatocytes via the activation of YAP1 signaling, and blockade of YAP1 abolished the LPS-induced cell stemness and upregulation of pluripotent markers. CONCLUSIONS: Our study implies a correlation between LPS/TLR4/YAP1 signaling and cell stemness, and LPS was shown to be involved in stemness maintenance of hepatocytes in the PV area. LPS might be used to induce the dedifferentiation of mature hepatocytes into progenitor-like cells for repair of liver injury.

Oncostatin M promotes hepatic progenitor cell activation and hepatocarcinogenesis via macrophage-derived tumor necrosis factor-α.

Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68+ macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis.

Single-parameter-tuned synthesis for shape-controlled gold nanocrystals stimulated by iron carbonyl.

Shape-controlled synthesis is essential for functional nanomaterials, allowing deeper insights intothe relationship between the structures and the catalytic properties. Synthesis of nanocrystals with particular morphologies are usually studied independently among various synthetic methods, those underline that different surface capping ligands or shape-directing agents bring about disparate shapes. However, a single quantitative parameter method is still lacking to realize precise control of well-defined morphology nanocrystals, especially anisotropic structures, which is essential to understanding the growth process of nanocrystals. Herein, we proposed a single-parameter-tuned synthesis strategy for preparation of shape-controlled gold nanocrystals by regulating the amount of iron carbonyl, by which we produced highly monodisperse Au nanocrystals with various shapes in organic phase including nanoplates (diameter of 16.02 ± 1.13 nm and thickness of 5.35 ± 0.58 nm), nanorods (length of 37.53 ± 3.73 nm and width of 5.26 ± 0.37 nm) and nanospheres (diameter of 8.26 ± 0.38 nm). The single-parameter-tuned method reveals the dual roles of iron carbonyl for controlling the shapes of gold nanocrystals including reductant and oxidative etchant and empowers versatility in synthetic methodology for other noble metals. Moreover, catalytic activity shifting in shapes of nanocrystals was revealed based on the reduction of 4-nitrophenol, showing that the as-synthesized Au nanoplates displayed the enhanced catalytic performance with the lowest activation energy. Our work provides a brand-new pathway for shape-controlled synthesis of noble-metal nanocrystals and has a strong practical value in application fields.